Since the development of the birth control pill for women, the past several decades have seen few advances in contraception. Furthermore, there is still no effective oral contraceptive pill for men. As stated in Healthy People 2010, "contraceptive research and development efforts must be expanded to bring new methods to the market." Thus, we need more effective, inexpensive, long-acting, and easily administered contraceptives, especially for men. In this proposal, we will focus on four intriguing and evolutionarily-conserved proteins that we hypothesize are outstanding targets for novel contraceptives. Knockout studies have demonstrated that mice lacking GASZ, VASA, TEX14, and STYX have a block at different points in spermatogenesis ranging from spermatocytes to spermatids, resulting in sterility. With the aid of our collaborators, Drs. Angela Koehler, Peter Davies, and Laising Yen, the overall goal of this research proposal from the Matzuk laboratory is to identify small molecules and chemical analogs that bind to these spermatogenic-specific proteins to block their function and/or disrupt protein:protein complexes, thereby causing a contraceptive effect. Our overall hypothesis is that we will rapidly identify multiple lead compounds that are directed at these unique and essential spermatogenic proteins and can be used to synthesize an assortment of oral and implantable contraceptives for men. The Specific Aims of these proposed U01 studies are: 1) Use small molecule microarrays and 2-hybrid screening assays to identify small molecules that bind GASZ, VASA, TEX14, or STYX and/or block key protein:protein interactions;and 2) Perform in vitro, in vivo, and computational screens to identify the most promising male contraceptives. Our studies are the first of their kind to use small molecule microarrays and mammalian 2-hybrid screening assays to identify small molecules that can act as contraceptives. We have put together a strong multidisciplinary group of scientists to tackle this important public health problem, and as a result, we believe that we can generate several novel contraceptives that will target unique proteins, structures, and processes in the germline in men. PUBLIC RELEVANCE: Despite the rapid increase in the world's population, the high rate of unintended pregnancies in U.S. teenagers (1 million per year), and the staggering cost to the American taxpayer of these unintended pregnancies ($7-$15 billion per year), there is no oral contraceptive for men. This application will focus on the identification of small molecules that target the male germline. Our studies are unique since they will use small molecule microarrays and protein:protein interaction assays to identify and characterize drugs that cause their contraceptive effect by inhibiting specific structures or pathways during spermatogenesis.